bims-tucedo 2022-09-11 papers

bims-tucedo

Biomed News

on Tumor cell dormancy

Issue of 2022–09–11
twenty-two papers selected by
Isabel Puig Borreil, Vall d’Hebron Institute of Oncology

The spindle assembly checkpoint is a therapeutic vulnerability of CDK4/6 inhibitor-resistant ER+ breast cancer with mitotic aberrations.
ALKBH5-mediated m6A demethylation of GLUT4 mRNA promotes glycolysis and resistance to HER2-targeted therapy in breast cancer.
An exercise-induced metabolic shield in distant organs blocks cancer progression and metastatic dissemination.
High p16 expression and heterozygous RB1 loss are biomarkers for CDK4/6 inhibitor resistance in ER+ breast cancer.
The cAMP/PKA/CREB and TGF-β/SMAD4 pathways regulate stemness and metastatic potential in colorectal cancer cells.
Targeted immunotherapy against distinct cancer-associated fibroblasts overcomes treatment resistance in refractory HER2+ breast tumors.
A novel selective inhibitor JBI-589 targets PAD4-mediated neutrophil migration to suppress tumor progression.
Connexins orchestrate progression of breast cancer metastasis to the brain by promoting FAK activation.
Ectopic JAK-STAT activation enables the transition to a stem-like and multilineage state conferring AR-targeted therapy resistance.
MET-induced CD73 restrains STING-mediated immunogenicity of EGFR-mutant lung cancer.
Comparative roadmaps of reprogramming and oncogenic transformation identify Bcl11b and Atoh8 as broad regulators of cellular plasticity.
Increased glucose metabolism in TAMs fuels O-GlcNAcylation of lysosomal Cathepsin B to promote cancer metastasis and chemoresistance.
Miat and interacting protein Metadherin maintain a stem-like niche to promote medulloblastoma tumorigenesis and treatment resistance.
MYBL2 promotes proliferation and metastasis of bladder cancer through transactivation of CDCA3.
Structural disruption of BAF chromatin remodeller impairs neuroblastoma metastasis by reverting an invasiveness epigenomic program.
Genomics to select treatment for patients with metastatic breast cancer.
Liquid biopsy detects early molecular response and predicts benefit to first-line chemotherapy plus cetuximab in metastatic colorectal cancer: PLATFORM-B study.
Treatment options for metastatic hormone-sensitive prostate cancer.
Precision medicine improves outcomes in metastatic breast cancer.
Cancer genome and tumor microenvironment: Reciprocal crosstalk shapes lung cancer plasticity.
CPEB3 suppresses gastric cancer progression by inhibiting ADAR1-mediated RNA editing via localizing ADAR1 mRNA to P bodies.
Preclinical and clinical efficacy of trastuzumab deruxtecan in breast cancer brain metastases.

Sci Adv. 2022 Sep 09. 8(36): eabq4293

The spindle assembly checkpoint is a therapeutic vulnerability of CDK4/6 inhibitor-resistant ER+ breast cancer with mitotic aberrations.

Isabel Soria-Bretones, Kelsie L Thu, Jennifer Silvester, Jennifer Cruickshank, Samah El Ghamrasni, Wail Ba-Alawi, Graham C Fletcher, Reza Kiarash, Mitchell J Elliott, Jordan J Chalmers, Andrea C Elia, Albert Cheng, April A N Rose, Mark R Bray, Benjamin Haibe-Kains, Tak W Mak, David W Cescon.

Inhibitors of cyclin-dependent kinases 4 and 6 (CDK4/6i) are standard first-line treatments for metastatic ER+ breast cancer. However, acquired resistance to CDK4/6i invariably develops, and the molecular phenotypes and exploitable vulnerabilities associated with resistance are not yet fully characterized. We developed a panel of CDK4/6i-resistant breast cancer cell lines and patient-derived organoids and demonstrate that a subset of resistant models accumulates mitotic segregation errors and micronuclei, displaying increased sensitivity to inhibitors of mitotic checkpoint regulators TTK and Aurora kinase A/B. RB1 loss, a well-recognized mechanism of CDK4/6i resistance, causes such mitotic defects and confers enhanced sensitivity to TTK inhibition. In these models, inhibition of TTK with CFI-402257 induces premature chromosome segregation, leading to excessive mitotic segregation errors, DNA damage, and cell death. These findings nominate the TTK inhibitor CFI-402257 as a therapeutic strategy for a defined subset of ER+ breast cancer patients who develop resistance to CDK4/6i.

DOI: https://doi.org/10.1126/sciadv.abq4293
Cancer Res. 2022 Sep 07. pii: CAN-22-0800. [Epub ahead of print]

ALKBH5-mediated m6A demethylation of GLUT4 mRNA promotes glycolysis and resistance to HER2-targeted therapy in breast cancer.

Hao Liu, Hui Lyu, Guanmin Jiang, Danyang Chen, Sanbao Ruan, Shuang Liu, Lukun Zhou, Mingqiang Yang, Shanshan Zeng, Zhimin He, Hongsheng Wang, Hongsheng Li, Guopei Zheng, Bolin Liu.

Resistance to HER2-targeted therapy represents a significant challenge for the successful treatment of breast cancer patients with HER2-positive tumors. Through a global mass spectrometry-based proteomics approach, we discovered that the expression of the N6-methyladenosine (m6A) demethylase ALKBH5 was significantly upregulated in HER2-targeted therapy-resistant breast cancer cells. Elevated expression of ALKBH5 was sufficient to confer resistance to HER2-targeted therapy, and specific knockdown of ALKBH5 rescued the efficacy of trastuzumab and lapatinib in resistant breast cancer cells. Mechanistically, ALKBH5 promoted m6A demethylation of GLUT4 mRNA and increased GLUT4 mRNA stability in a YTHDF2-dependent manner, resulting in enhanced glycolysis in resistant breast cancer cells. In breast cancer tissues obtained from patients with poor response to HER2-targeted therapy, increased expression of ALKBH5 or GLUT4 was observed and was significantly associated with poor prognosis in the patients. Moreover, suppression of GLUT4 via genetic knockdown or pharmacological targeting with a specific inhibitor profoundly restored the response of resistant breast cancer cells to trastuzumab and lapatinib both in vitro and in vivo. In conclusion, ALKBH5-mediated m6A demethylation of GLUT4 mRNA promotes resistance to HER2-targeted therapy, and targeting the ALKBH5/GLUT4 axis has therapeutic potential for treating breast cancer patients refractory to HER2-targeted therapies.

DOI: https://doi.org/10.1158/0008-5472.CAN-22-0800
Cancer Res. 2022 Sep 09. pii: CAN-22-0237. [Epub ahead of print]

An exercise-induced metabolic shield in distant organs blocks cancer progression and metastatic dissemination.

Danna Sheinboim, Shivang Parikh, Paulee Manich, Irit Markus, Sapir Dahan, Roma Parikh, Elisa Stubbs, Gali Cohen, Valentina Zemser-Werner, Rachel E Bell, Sara Arciniegas Ruiz, Ruth Percik, Ronen Brenner, Stav Leibou, Hananya Vaknine, Gali Arad, Yariv Gerber, Lital Keinan Boker, Tal Shimony, Lior Bikovski, Nir Goldstein, Keren Constantini, Sapir Labes, Shimonov Mordechai, Hila Doron, Ariel Ionescu, Tamar Ziv, Eran Nizri, Guy Choshen, Hagit Eldar-Finkelman, Yuval Tabach, Aharon Helman, Shamgar Ben-Eliyahu, Neta Erez, Eran Perlson, Tamar Geiger, Danny Ben-Zvi, Mehdi Khaled, Yftach Gepner, Carmit Levy.

Exercise prevents cancer incidence and recurrence, yet the underlying mechanism behind this relationship remains mostly unknown. Here we report that exercise induces metabolic reprogramming of internal organs that increases nutrient demand and protects against metastatic colonization by limiting nutrient availability to the tumor, generating an exercise-induced metabolic shield. Proteomic and ex vivo metabolic capacity analyses of murine internal organs revealed that exercise induces catabolic processes, glucose uptake, mitochondrial activity, and GLUT expression. Proteomic analysis of routinely active human subject plasma demonstrated increased carbohydrate utilization following exercise. Epidemiological data from a 20-year prospective study of a large human cohort of initially cancer-free participants revealed that exercise prior to cancer initiation had a modest impact on cancer incidence in low metastatic stages but significantly reduced the likelihood of highly metastatic cancer. In three models of melanoma in mice, exercise prior to cancer injection significantly protected against metastases in distant organs. The protective effects of exercise were dependent on mTOR activity, and inhibition of the mTOR pathway with rapamycin treatment ex vivo reversed the exercise-induced metabolic shield. Under limited glucose conditions, active stroma consumed significantly more glucose at the expense of the tumor. Collectively, these data suggest a clash between the metabolic plasticity of cancer and exercise-induced metabolic reprogramming of the stroma, raising an opportunity to block metastasis by challenging the metabolic needs of the tumor.

DOI: https://doi.org/10.1158/0008-5472.CAN-22-0237
Nat Commun. 2022 Sep 07. 13(1): 5258

High p16 expression and heterozygous RB1 loss are biomarkers for CDK4/6 inhibitor resistance in ER+ breast cancer.

Marta Palafox, Laia Monserrat, Meritxell Bellet, Guillermo Villacampa, Abel Gonzalez-Perez, Mafalda Oliveira, Fara Brasó-Maristany, Nusaibah Ibrahimi, Srinivasaraghavan Kannan, Leonardo Mina, Maria Teresa Herrera-Abreu, Andreu Òdena, Mònica Sánchez-Guixé, Marta Capelán, Analía Azaro, Alejandra Bruna, Olga Rodríguez, Marta Guzmán, Judit Grueso, Cristina Viaplana, Javier Hernández, Faye Su, Kui Lin, Robert B Clarke, Carlos Caldas, Joaquín Arribas, Stefan Michiels, Alicia García-Sanz, Nicholas C Turner, Aleix Prat, Paolo Nuciforo, Rodrigo Dienstmann, Chandra S Verma, Nuria Lopez-Bigas, Maurizio Scaltriti, Monica Arnedos, Cristina Saura, Violeta Serra.

CDK4/6 inhibitors combined with endocrine therapy have demonstrated higher antitumor activity than endocrine therapy alone for the treatment of advanced estrogen receptor-positive breast cancer. Some of these tumors are de novo resistant to CDK4/6 inhibitors and others develop acquired resistance. Here, we show that p16 overexpression is associated with reduced antitumor activity of CDK4/6 inhibitors in patient-derived xenografts (n = 37) and estrogen receptor-positive breast cancer cell lines, as well as reduced response of early and advanced breast cancer patients to CDK4/6 inhibitors (n = 89). We also identified heterozygous RB1 loss as biomarker of acquired resistance and poor clinical outcome. Combination of the CDK4/6 inhibitor ribociclib with the PI3K inhibitor alpelisib showed antitumor activity in estrogen receptor-positive non-basal-like breast cancer patient-derived xenografts, independently of PIK3CA, ESR1 or RB1 mutation, also in drug de-escalation experiments or omitting endocrine therapy. Our results offer insights into predicting primary/acquired resistance to CDK4/6 inhibitors and post-progression therapeutic strategies.

DOI: https://doi.org/10.1038/s41467-022-32828-6
Cancer Res. 2022 Sep 06. pii: CAN-22-1369. [Epub ahead of print]

The cAMP/PKA/CREB and TGF-β/SMAD4 pathways regulate stemness and metastatic potential in colorectal cancer cells.

Teruaki Fujishita, Yasushi Kojima, Rie Kajino-Sakamoto, Emi Mishiro-Sato, Yasuhiro Shimizu, Waki Hosoda, Rui Yamaguchi, Makoto Mark Taketo, Masahiro Aoki.

Metastasis is responsible for the majority of deaths of cancer patients. However, mechanisms governing metastasis in colorectal cancer (CRC) remain largely unknown. Here we investigated how CRC cells acquire metastatic potential using a novel mouse model of CRC that spontaneously develops liver metastasis, generated by introducing sporadic mutations of Ctnnb1, Kras, Trp53, and Smad4 (CKPS) genes. Proteomic analyses revealed elevated expression of CRC stem cell markers ALCAM (CD166) and PROM1 (CD133) in CRC cells from the metastatic model compared with those from a non-metastatic model. Spleen-to-liver metastasis assays using CRC cells derived from the CKPS model (CKPS cells) demonstrated the functional importance of ALCAM and PROM1 in initiating metastasis. Genetic and pharmacological analyses using CKPS cells in 2D and spheroid culture revealed that expression of ALCAM and PROM1 is regulated positively and negatively by the cAMP/PKA/CREB and TGF-β/SMAD4 pathways, respectively. Consistently, phospho-CREB was expressed in both primary and metastatic lesions of CKPS mice and CRC patients, and knockout of CREB in CKPS cells reduced their spheroid-forming and metastasis-initiating abilities. Treatment with a CREB inhibitor potentiated the effect of irinotecan in suppressing liver metastasis by CKPS cells. These results reveal the essential roles of ALCAM and PROM1, as well as their upstream regulators, the cAMP/PKA/CREB and TGF-β/SMAD4 pathways, in maintaining the stemness and metastatic potential of CRC cells and indicate that CREB inhibition may be a potential therapeutic strategy against metastatic CRC.

DOI: https://doi.org/10.1158/0008-5472.CAN-22-1369
Nat Commun. 2022 Sep 09. 13(1): 5310

Targeted immunotherapy against distinct cancer-associated fibroblasts overcomes treatment resistance in refractory HER2+ breast tumors.

Elisa I Rivas, Jenniffer Linares, Melissa Zwick, Andrea Gómez-Llonin, Marc Guiu, Anna Labernadie, Jordi Badia-Ramentol, Anna Lladó, Lídia Bardia, Iván Pérez-Núñez, Carolina Martínez-Ciarpaglini, Noelia Tarazona, Anna Sallent-Aragay, Marta Garrido, Toni Celià-Terrassa, Octavio Burgués, Roger R Gomis, Joan Albanell, Alexandre Calon.

About 50% of human epidermal growth factor receptor 2 (HER2)+ breast cancer patients do not benefit from HER2-targeted therapy and almost 20% of them relapse after treatment. Here, we conduct a detailed analysis of two independent cohorts of HER2+ breast cancer patients treated with trastuzumab to elucidate the mechanisms of resistance to anti-HER2 monoclonal antibodies. In addition, we develop a fully humanized immunocompetent model of HER2+ breast cancer recapitulating ex vivo the biological processes that associate with patients' response to treatment. Thanks to these two approaches, we uncover a population of TGF-beta-activated cancer-associated fibroblasts (CAF) specific from tumors resistant to therapy. The presence of this cellular subset related to previously described myofibroblastic (CAF-S1) and podoplanin+ CAF subtypes in breast cancer associates with low IL2 activity. Correspondingly, we find that stroma-targeted stimulation of IL2 pathway in unresponsive tumors restores trastuzumab anti-cancer efficiency. Overall, our study underscores the therapeutic potential of exploiting the tumor microenvironment to identify and overcome mechanisms of resistance to anti-cancer treatment.

DOI: https://doi.org/10.1038/s41467-022-32782-3
Cancer Res. 2022 Sep 07. pii: CAN-21-4045. [Epub ahead of print]

A novel selective inhibitor JBI-589 targets PAD4-mediated neutrophil migration to suppress tumor progression.

Hui Deng, Cindy Lin, Laura Garcia-Gerique, Shuyu Fu, Zachary Cruz, Erin E Bonner, Matthew Rosenwasser, Sridharan Rajagopal, M Naveen Sadhu, Chandru Gajendran, Mohd Zainuddin, Ramachandraiah Gosu, Dhanalakshmi Sivanandhan, Miriam A Shelef, Brian Nam, Dan T Vogl, Dmitry I Gabrilovich, Yulia Nefedova.

Neutrophils are closely involved in the regulation of tumor progression and formation of pre-metastatic niches. However, the mechanisms of their involvement and therapeutic regulation of these processes remain elusive. Here, we report a critical role of neutrophil peptidylarginine deiminase 4 (PAD4) in neutrophil migration in cancer. In several transplantable and genetically engineered mouse models, tumor growth was accompanied by significantly elevated enzymatic activity of neutrophil PAD4. Targeted deletion of PAD4 in neutrophils markedly decreased the intratumoral abundance of neutrophils and led to delayed growth of primary tumors and dramatically reduced lung metastases. PAD4 mediated neutrophil accumulation by regulating the expression of the major chemokine receptor CXCR2. PAD4 expression and activity as well as CXCR2 expression were significantly upregulated in neutrophils from patients with lung and colon cancers compared to healthy donors, and PAD4 and CXCR2 expression were positively correlated in neutrophils from cancer patients. In tumor-bearing mice, pharmacological inhibition of PAD4 with the novel PAD4 isoform-selective small molecule inhibitor JBI-589 resulted in reduced CXCR2 expression and blocked neutrophil chemotaxis. In mouse tumor models, targeted deletion of PAD4 in neutrophils or pharmacological inhibition of PAD4 with JBI-589 reduced both primary tumor growth and lung metastases and substantially enhanced the effect of immune checkpoint inhibitors. Taken together, these results suggest a therapeutic potential of targeting PAD4 in cancer.

DOI: https://doi.org/10.1158/0008-5472.CAN-21-4045
Sci Transl Med. 2022 Sep 07. 14(661): eaax8933

Connexins orchestrate progression of breast cancer metastasis to the brain by promoting FAK activation.

Girieca Lorusso, Christof B Wyss, François Kuonen, Nicola Vannini, Clotilde Billottet, Nathalie Duffey, Raphael Pineau, Qiang Lan, Pratyaksha Wirapati, David Barras, Alessandro Tancredi, Ruth Lyck, Hans-Anton Lehr, Britta Engelhardt, Mauro Delorenzi, Andreas Bikfalvi, Curzio Rüegg.

Brain metastasis is a complication of increasing incidence in patients with breast cancer at advanced disease stage. It is a severe condition characterized by a rapid decline in quality of life and poor prognosis. There is a critical clinical need to develop effective therapies to prevent and treat brain metastases. Here, we describe a unique and robust spontaneous preclinical model of breast cancer metastasis to the brain (4T1-BM2) in mice that has been instrumental in uncovering molecular mechanisms guiding metastatic dissemination and colonization of the brain. Key experimental findings were validated in the additional murine D2A1-BM2 model and in human MDA231-BrM2 model. Gene expression analyses and functional studies, coupled with clinical transcriptomic and histopathological investigations, identified connexins (Cxs) and focal adhesion kinase (FAK) as master molecules orchestrating breast cancer colonization of the brain. Cx31 promoted homotypic tumor cell adhesion, heterotypic tumor-astrocyte interaction, and FAK phosphorylation. FAK signaling prompted NF-κB activation inducing Lamc2 expression and laminin 332 (laminin 5) deposition, α6 integrin-mediated adhesion, and sustained survival and growth within brain parenchyma. In the MDA231-BrM2 model, the human homologous molecules CX43, LAMA4, and α3 integrin were involved. Systemic treatment with FAK inhibitors reduced brain metastasis progression. In conclusion, we report a spontaneous model of breast cancer metastasis to the brain and identified Cx-mediated FAK-NF-κB signaling as a mechanism promoting cell-autonomous and microenvironmentally controlled cell survival for brain colonization. Considering the limited therapeutic options for brain metastatic disease in cancer patients, we propose FAK as a therapeutic candidate to further pursue in the clinic.

DOI: https://doi.org/10.1126/scitranslmed.aax8933
Nat Cancer. 2022 Sep 05.

Ectopic JAK-STAT activation enables the transition to a stem-like and multilineage state conferring AR-targeted therapy resistance.

Su Deng, Choushi Wang, Yunguan Wang, Yaru Xu, Xiaoling Li, Nickolas A Johnson, Atreyi Mukherji, U-Ging Lo, Lingfan Xu, Julisa Gonzalez, Lauren A Metang, Jianfeng Ye, Carla Rodriguez Tirado, Kathia Rodarte, Yinglu Zhou, Zhiqun Xie, Carlos Arana, Valli Annamalai, Xihui Liu, Donald J Vander Griend, Douglas Strand, Jer-Tsong Hsieh, Bo Li, Ganesh Raj, Tao Wang, Ping Mu.

Emerging evidence indicates that various cancers can gain resistance to targeted therapies by acquiring lineage plasticity. Although various genomic and transcriptomic aberrations correlate with lineage plasticity, the molecular mechanisms enabling the acquisition of lineage plasticity have not been fully elucidated. We reveal that Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling is a crucial executor in promoting lineage plasticity-driven androgen receptor (AR)-targeted therapy resistance in prostate cancer. Importantly, ectopic JAK-STAT activation is specifically required for the resistance of stem-like subclones expressing multilineage transcriptional programs but not subclones exclusively expressing the neuroendocrine-like lineage program. Both genetic and pharmaceutical inhibition of JAK-STAT signaling resensitizes resistant tumors to AR-targeted therapy. Together, these results suggest that JAK-STAT are compelling therapeutic targets for overcoming lineage plasticity-driven AR-targeted therapy resistance.

DOI: https://doi.org/10.1038/s43018-022-00431-9
Cancer Res. 2022 Sep 06. pii: CAN-22-0770. [Epub ahead of print]

MET-induced CD73 restrains STING-mediated immunogenicity of EGFR-mutant lung cancer.

Ryohei Yoshida, Maria Saigi, Tetsuo Tani, Benjamin F Springer, Hirofumi Shibata, Shunsuke Kitajima, Navin R Mahadevan, Marco Campisi, William Kim, Yoshihisa Kobayashi, Tran C Thai, Koji Haratani, Yurie Yamamoto, Shriram K Sundararaman, Erik H Knelson, Amir Vajdi, Israel Canadas, Ravindra Uppaluri, Cloud P Paweletz, Juan J Miret, Patrick H Lizotte, Prafulla C Gokhale, Pasi A Janne, David A Barbie.

Immunotherapy has shown limited efficacy in EGFR-mutated lung cancer patients. Efforts to enhance the immunogenicity of EGFR-mutated lung cancer have been unsuccessful to date. Here, we discover that MET amplification, the most common mechanism of resistance to third generation EGFR tyrosine kinase inhibitors (TKI), activates tumor cell STING, an emerging determinant of cancer immunogenicity. However, STING activation was restrained by the ectonucleosidase CD73, which is induced in MET-amplified, EGFR TKI-resistant cells. Systematic genomic analyses and cell line studies confirmed upregulation of CD73 in MET-amplified and MET-activated lung cancer contexts, which depends on co-induction of FOSL1. Pemetrexed (PEM), which is commonly used following EGFR-TKI treatment failure, was identified as an effective potentiator of STING-dependent TBK1-IRF3-STAT1 signaling in MET-amplified, EGFR TKI-resistant cells. However, PEM treatment also induced adenosine production, which inhibited T-cell responsiveness. In an allogenic humanized mouse model, CD73 deletion enhanced immunogenicity of MET-amplified, EGFR TKI-resistant cells, and PEM treatment promoted robust responses regardless of CD73 status. Using a physiologic antigen recognition model, inactivation of CD73 significantly increased antigen-specific CD8+ T-cell immunogenicity following PEM treatment. These data reveal that combined PEM and CD73 inhibition can co-opt tumor cell STING induction in TKI resistant EGFR-mutated lung cancers and promote immunogenicity.

DOI: https://doi.org/10.1158/0008-5472.CAN-22-0770
Nat Cell Biol. 2022 Sep 08.

Comparative roadmaps of reprogramming and oncogenic transformation identify Bcl11b and Atoh8 as broad regulators of cellular plasticity.

A Huyghe, G Furlan, J Schroeder, E Cascales, A Trajkova, M Ruel, F Stüder, M Larcombe, Y Bo Yang Sun, F Mugnier, L De Matteo, A Baygin, J Wang, Y Yu, N Rama, B Gibert, J Kielbassa, L Tonon, P Wajda, N Gadot, M Brevet, M Siouda, P Mulligan, R Dante, P Liu, H Gronemeyer, M Mendoza-Parra, J M Polo, F Lavial.

Coordinated changes of cellular plasticity and identity are critical for pluripotent reprogramming and oncogenic transformation. However, the sequences of events that orchestrate these intermingled modifications have never been comparatively dissected. Here, we deconvolute the cellular trajectories of reprogramming (via Oct4/Sox2/Klf4/c-Myc) and transformation (via Ras/c-Myc) at the single-cell resolution and reveal how the two processes intersect before they bifurcate. This approach led us to identify the transcription factor Bcl11b as a broad-range regulator of cell fate changes, as well as a pertinent marker to capture early cellular intermediates that emerge simultaneously during reprogramming and transformation. Multiomics characterization of these intermediates unveiled a c-Myc/Atoh8/Sfrp1 regulatory axis that constrains reprogramming, transformation and transdifferentiation. Mechanistically, we found that Atoh8 restrains cellular plasticity, independent of cellular identity, by binding a specific enhancer network. This study provides insights into the partitioned control of cellular plasticity and identity for both regenerative and cancer biology.

DOI: https://doi.org/10.1038/s41556-022-00986-w
Cancer Cell. 2022 Aug 30. pii: S1535-6108(22)00376-2. [Epub ahead of print]

Increased glucose metabolism in TAMs fuels O-GlcNAcylation of lysosomal Cathepsin B to promote cancer metastasis and chemoresistance.

Qingzhu Shi, Qicong Shen, Yanfang Liu, Yang Shi, Wenwen Huang, Xi Wang, Zhiqing Li, Yangyang Chai, Hao Wang, Xiangjia Hu, Nan Li, Qian Zhang, Xuetao Cao.

  How glucose metabolism remodels pro-tumor functions of tumor-associated macrophages (TAMs) needs further investigation. Here we show that M2-like TAMs bear the highest individual capacity to take up intratumoral glucose. Their increased glucose uptake fuels hexosamine biosynthetic pathway-dependent O-GlcNAcylation to promote cancer metastasis and chemoresistance. Glucose metabolism promotes O-GlcNAcylation of the lysosome-encapsulated protease Cathepsin B at serine 210, mediated by lysosome-localized O-GlcNAc transferase (OGT), elevating mature Cathepsin B in macrophages and its secretion in the tumor microenvironment (TME). Loss of OGT in macrophages reduces O-GlcNAcylation and mature Cathepsin B in the TME and disrupts cancer metastasis and chemoresistance. Human TAMs with high OGT are positively correlated with Cathepsin B expression, and both levels predict chemotherapy response and prognosis of individuals with cancer. Our study reports the biological and potential clinical significance of glucose metabolism in tumor-promoting TAMs and reveals insights into the underlying mechanisms.

Keywords:  O-GlcNAc transferase; O-GlcNAcylation; cathepsin B; glucose metabolism; lysosome; metastasis; tumor-associated macrophages

DOI:  https://doi.org/10.1016/j.ccell.2022.08.012
Proc Natl Acad Sci U S A. 2022 Sep 13. 119(37): e2203738119

Miat and interacting protein Metadherin maintain a stem-like niche to promote medulloblastoma tumorigenesis and treatment resistance.

Kai-Lin Peng, Harish N Vasudevan, Dennis T Lockney, Rachel Baum, Ronald C Hendrickson, David R Raleigh, Adam M Schmitt.

  Long noncoding RNAs (lncRNAs) play essential roles in the development and progression of many cancers. However, the contributions of lncRNAs to medulloblastoma (MB) remain poorly understood. Here, we identify Miat as an lncRNA enriched in the sonic hedgehog group of MB that is required for maintenance of a treatment-resistant stem-like phenotype in the disease. Loss of Miat results in the differentiation of tumor-initiating, stem-like MB cells and enforces the differentiation of tumorigenic stem-like MB cells into a nontumorigenic state. Miat expression in stem-like MB cells also facilitates treatment resistance by down-regulating p53 signaling and impairing radiation-induced cell death, which can be reversed by therapeutic inhibition of Miat using antisense oligonucleotides. Mechanistically, the RNA binding protein Metadherin (Mtdh), previously linked to resistance to cytotoxic therapy in cancer, binds to Miat in stem-like MB cells. Like the loss of Miat, the loss of Mtdh reduces tumorigenicity and increases sensitivity to radiation-induced death in stem-like MB cells. Moreover, Miat and Mtdh function to regulate the biogenesis of several microRNAs and facilitate tumorigenesis and treatment resistance. Taken together, these data reveal an essential role for the lncRNA Miat in sustaining a treatment-resistant pool of tumorigenic stem-like MB cells.

Keywords:  Metadherin; Miat; long noncoding RNA; medulloblastoma

DOI:  https://doi.org/10.1073/pnas.2203738119
Oncogene. 2022 Sep 07.

MYBL2 promotes proliferation and metastasis of bladder cancer through transactivation of CDCA3.

Wei Liu, Dexin Shen, Lingao Ju, Renjie Zhang, Wenzhi Du, Wan Jin, Kangping Xiong, Gang Wang, Kaiyu Qian, Yi Zhang, Yu Xiao, Xinghuan Wang.

The transcription factor MYB proto-oncogene like 2 (MYBL2) is critical in regulating gene expression and tumorigenesis. However, the biological function of MYBL2 in bladder cancer (BLCA) remains to be elucidated. Here, we first revealed that MYBL2 was elevated in BLCA tissues and significantly correlated with clinicopathological parameters and cancer-specific survival in BLCA patients. Phenotypic assays showed that MYBL2 deficiency suppressed the proliferation and migration of BLCA cells in vitro and in vivo, whereas MYBL2 overexpression contributed to the opposite phenotype. Mechanistically, MYBL2 could bind to the promoter of its downstream target gene cell division cycle-associated protein 3 (CDCA3) and transactivate it, which in turn promoted the malignant phenotype of BLCA cells. Further investigations revealed that MYBL2 interacted with forkhead box M1 (FOXM1) to co-regulate the transcription of CDCA3. In addition, MYBL2/FOXM1 and CDCA3 might activate Wnt/β-catenin signaling, thereby promoting the malignant phenotype of BLCA cells. In conclusion, the current study identifies MYBL2 as an oncogene in BLCA. MYBL2 can accelerate the proliferation and metastasis of BLCA through the transactivation of CDCA3.

DOI: https://doi.org/10.1038/s41388-022-02456-x
Mol Cancer. 2022 Sep 03. 21(1): 175

Structural disruption of BAF chromatin remodeller impairs neuroblastoma metastasis by reverting an invasiveness epigenomic program.

Carlos Jiménez, Roberta Antonelli, Mariona Nadal-Ribelles, Laura Devis-Jauregui, Pablo Latorre, Carme Solé, Marc Masanas, Adrià Molero-Valenzuela, Aroa Soriano, Josep Sánchez de Toledo, David Llobet-Navas, Josep Roma, Francesc Posas, Eulàlia de Nadal, Soledad Gallego, Lucas Moreno, Miguel F Segura.

   BACKGROUND: Epigenetic programming during development is essential for determining cell lineages, and alterations in this programming contribute to the initiation of embryonal tumour development. In neuroblastoma, neural crest progenitors block their course of natural differentiation into sympathoadrenergic cells, leading to the development of aggressive and metastatic paediatric cancer. Research of the epigenetic regulators responsible for oncogenic epigenomic networks is crucial for developing new epigenetic-based therapies against these tumours. Mammalian switch/sucrose non-fermenting (mSWI/SNF) ATP-dependent chromatin remodelling complexes act genome-wide translating epigenetic signals into open chromatin states. The present study aimed to understand the contribution of mSWI/SNF to the oncogenic epigenomes of neuroblastoma and its potential as a therapeutic target.
METHODS: Functional characterisation of the mSWI/SNF complexes was performed in neuroblastoma cells using proteomic approaches, loss-of-function experiments, transcriptome and chromatin accessibility analyses, and in vitro and in vivo assays.
RESULTS: Neuroblastoma cells contain three main mSWI/SNF subtypes, but only BRG1-associated factor (BAF) complex disruption through silencing of its key structural subunits, ARID1A and ARID1B, impairs cell proliferation by promoting cell cycle blockade. Genome-wide chromatin remodelling and transcriptomic analyses revealed that BAF disruption results in the epigenetic repression of an extensive invasiveness-related expression program involving integrins, cadherins, and key mesenchymal regulators, thereby reducing adhesion to the extracellular matrix and the subsequent invasion in vitro and drastically inhibiting the initiation and growth of neuroblastoma metastasis in vivo.
CONCLUSIONS: We report a novel ATPase-independent role for the BAF complex in maintaining an epigenomic program that allows neuroblastoma invasiveness and metastasis, urging for the development of new BAF pharmacological structural disruptors for therapeutic exploitation in metastatic neuroblastoma.

Keywords:  Cancer; Chromatin remodelling; Epigenetics; Epigenomics; Metastasis; Neuroblastoma; SWI/SNF

DOI:  https://doi.org/10.1186/s12943-022-01643-4
Nature. 2022 Sep 07.

Genomics to select treatment for patients with metastatic breast cancer.

Fabrice Andre, Thomas Filleron, Maud Kamal, Fernanda Mosele, Monica Arnedos, Florence Dalenc, Marie-Paule Sablin, Mario Campone, Hervé Bonnefoi, Claudia Lefeuvre-Plesse, William Jacot, Florence Coussy, Jean-Marc Ferrero, George Emile, Marie-Ange Mouret-Reynier, Jean-Christophe Thery, Nicolas Isambert, Alice Mege, Philippe Barthelemy, Benoit You, Nawale Hajjaji, Ludovic Lacroix, Etienne Rouleau, Alicia Tran-Dien, Sandrine Boyault, Valery Attignon, Pierre Gestraud, Nicolas Servant, Christophe Le Tourneau, Linda Larbi Cherif, Isabelle Soubeyran, Filippo Montemurro, Alain Morel, Amelie Lusque, Marta Jimenez, Alexandra Jacquet, Anthony Gonçalves, Thomas Bachelot, Ivan Bieche.

Cancer progression is driven in part by genomic alterations1. The genomic characterization of cancers has shown interpatient heterogeneity regarding driver alterations2, leading to the concept that generation of genomic profiling in patients with cancer could allow the selection of effective therapies3,4. Although DNA sequencing has been implemented in practice, it remains unclear how to use its results. A total of 1,462 patients with HER2-non-overexpressing metastatic breast cancer were enroled to receive genomic profiling in the SAFIR02-BREAST trial. Two hundred and thirty-eight of these patients were randomized in two trials (nos. NCT02299999 and NCT03386162) comparing the efficacy of maintenance treatment5 with a targeted therapy matched to genomic alteration. Targeted therapies matched to genomics improves progression-free survival when genomic alterations are classified as level I/II according to the ESMO Scale for Clinical Actionability of Molecular Targets (ESCAT)6 (adjusted hazards ratio (HR): 0.41, 90% confidence interval (CI): 0.27-0.61, P < 0.001), but not when alterations are unselected using ESCAT (adjusted HR: 0.77, 95% CI: 0.56-1.06, P = 0.109). No improvement in progression-free survival was observed in the targeted therapies arm (unadjusted HR: 1.15, 95% CI: 0.76-1.75) for patients presenting with ESCAT alteration beyond level I/II. Patients with germline BRCA1/2 mutations (n = 49) derived high benefit from olaparib (gBRCA1: HR = 0.36, 90% CI: 0.14-0.89; gBRCA2: HR = 0.37, 90% CI: 0.17-0.78). This trial provides evidence that the treatment decision led by genomics should be driven by a framework of target actionability in patients with metastatic breast cancer.

DOI: https://doi.org/10.1038/s41586-022-05068-3
Clin Cancer Res. 2022 Sep 08. pii: CCR-22-1696. [Epub ahead of print]

Liquid biopsy detects early molecular response and predicts benefit to first-line chemotherapy plus cetuximab in metastatic colorectal cancer: PLATFORM-B study.

Joana Vidal, Maria Concepción Fernández-Rodríguez, David Casadevall, Pilar Garcia-Alfonso, David Páez, Marta Guix, Vicente Alonso, María Teresa Cano, Cristina Santos, Gema Durán, Elena Élez, Jose Luis Manzano, Rocio Garcia-Carbonero, Reyes Ferreiro-Monteagudo, Ferran Losa, Estela Pineda, Javier Sastre, Fernando Rivera, Beatriz Bellosillo, Josep Tabernero, Enrique Aranda, Ramon Salazar, Clara Montagut.

PURPOSE: Chemotherapy plus anti-EGFR is standard first-line therapy in RAS wt metastatic colorectal cancer (mCRC) but biomarkers of early response are clinically needed. We aimed to define the utility of ctDNA to assess early response in mCRC patients receiving first-line anti-EGFR therapy.
EXPERIMENTAL DESIGN: Prospective multicentric study of tissue RAS wt mCRC patients treated with first-line chemotherapy plus cetuximab undergoing sequential liquid biopsies. Baseline and early (C3) ctDNA were analyzed by NGS. Trunk mutations were assessed as surrogate marker of total tumor burden. RAS/BRAF/MEK/EGFR-ECD were considered mutations of resistance. ctDNA results were correlated with clinical outcome.
RESULTS: 100 patients were included. ctDNA was detected in 72% of patients baseline and 32% at C3. Decrease in ctDNA trunk mutations correlated with progression-free survival (PFS) (HR= 0.23 P=0.001). RAS/BRAF were the only resistant mutations detected at C3. An increase in the relative fraction of RAS/BRAF at C3 was followed by an expansion of the RAS clone until PD, and was associated with shorter PFS (HR= 10.5, P<0.001). The best predictor of response was combined analysis of trunk and resistant mutations at C3. Accordingly, patients with "early molecular response" (decrease in trunk and decrease in resistant mutations) had better response (77.5% vs. 25%, P=0.008) and longer PFS (HR=0.18, P<0.001) compared to patients with "early molecular progression" (increase in trunk and/or increase in resistant mutations).
CONCLUSIONS: ctDNA detects early molecular response and predicts benefit to chemotherapy plus cetuximab. A comprehensive NGS-based approach is recommended to integrate information on total disease burden and resistant mutations.

DOI: https://doi.org/10.1158/1078-0432.CCR-22-1696
Lancet Oncol. 2022 Sep 05. pii: S1470-2045(22)00520-4. [Epub ahead of print]

Treatment options for metastatic hormone-sensitive prostate cancer.

Louise Kostos, Declan G Murphy.

DOI: https://doi.org/10.1016/S1470-2045(22)00520-4
Nature. 2022 Sep 07.

Precision medicine improves outcomes in metastatic breast cancer.



Keywords:  Cancer; Genomics; Personalized medicine

DOI:  https://doi.org/10.1038/d41586-022-02276-9
Elife. 2022 Sep 08. pii: e79895. [Epub ahead of print]11

Cancer genome and tumor microenvironment: Reciprocal crosstalk shapes lung cancer plasticity.

Siavash Mansouri, Daniel Heylmann, Thorsten Stiewe, Michael Kracht, Rajkumar Savai.

  Lung cancer classification and treatment has been revolutionized by improving our understanding of driver mutations and the introduction of tumor microenvironment (TME)-associated immune checkpoint inhibitors. Despite the significant improvement of lung cancer patient survival in response to either oncogene-targeted therapy or anticancer immunotherapy, many patients show initial or acquired resistance to these new therapies. Recent advances in genome sequencing reveal that specific driver mutations favor the development of an immunosuppressive TME phenotype, which may result in unfavorable outcomes in lung cancer patients receiving immunotherapies. Clinical studies with follow-up after immunotherapy, assessing oncogenic driver mutations and the TME immune profile, not only reveal the underlying potential molecular mechanisms in the resistant lung cancer patients but also hold the key to better treatment choices and the future of personalized medicine. In this review, we discuss the crosstalk between cancer cell genomic features and the TME to reveal the impact of genetic alterations on the TME phenotype. We also provide insights into the regulatory role of cellular TME components in defining the genetic landscape of cancer cells during tumor development.

Keywords:  cancer biology; cancer genome; immunology; inflammation; lung cancer; tumor microenvironment

DOI:  https://doi.org/10.7554/eLife.79895
Oncogene. 2022 Sep 06.

CPEB3 suppresses gastric cancer progression by inhibiting ADAR1-mediated RNA editing via localizing ADAR1 mRNA to P bodies.

Jian Chen, Lu Li, Tian-Yu Liu, Hua-Feng Fu, Yuan-Hui Lai, Xiong Lei, Jun-Fa Xu, Ji-Shang Yu, Yu-Jian Xia, Tian-Hao Zhang, Dong-Jie Yang, Yu-Long He.

Deciphering the crosstalk between RNA-binding proteins and corresponding RNAs will provide a better understanding of gastric cancer (GC) progression. The comprehensive bioinformatics study identified cytoplasmic polyadenylation element-binding protein 3 (CPEB3) might play a vital role in GC progression. Then we found CPEB3 was downregulated in GC and correlated with prognosis. In addition, CPEB3 suppressed GC cell proliferation, invasion and migration in vitro, as well as tumor growth and metastasis in vivo. Mechanistic study demonstrated CPEB3 interacted with 3'-UTR of ADAR1 mRNA through binding to CPEC nucleotide element, and then inhibited its translation by localizing it to processing bodies (P bodies), eventually leading to the suppression of ADAR1-mediated RNA editing. Microscale thermophoresis assay further revealed that the direct interaction between CPEB3 and GW182, the P-body's major component, was through the 440-698AA region of CPEB3 binding to the 403-860AA region of GW182. Finally, AAV9-CPEB3 was developed and administrated in mouse models to assess its potential value in gene therapy. We found AAV9-CPEB3 inhibited GC growth and metastasis. Besides, AAV9-CPEB3 induced hydropic degeneration in mouse liver, but did not cause kidney damage. These findings concluded that CPEB3 suppresses GC progression by inhibiting ADAR1-mediated RNA editing via localizing ADAR1 mRNA to P bodies.

DOI: https://doi.org/10.1038/s41388-022-02454-z
Clin Cancer Res. 2022 Sep 08. pii: CCR-22-1138. [Epub ahead of print]

Preclinical and clinical efficacy of trastuzumab deruxtecan in breast cancer brain metastases.

Sheheryar Kabraji, Jing Ni, Sarah Sammons, Tianyu Li, Amanda E D Van Swearingen, Yanzhi Wang, Alyssa Pereslete, Liangge Hsu, Pamela J DiPiro, Christopher Lascola, Heather Moore, Melissa Hughes, Akshara S Raghavendra, Maria Gule-Monroe, Rashmi K Murthy, Eric P Winer, Carey K Anders, Jean J Zhao, Nancy U Lin.

PURPOSE: Brain metastases can occur in up to 50% of patients with metastatic HER2-positive breast cancer. Because patients with active brain metastases were excluded from previous pivotal clinical trials, the CNS activity of the antibody-drug conjugate (ADC), trastuzumab deruxtecan (T-DXd), is not well characterized.
EXPERIMENTAL DESIGN: We studied how T-DXd affects growth and overall survival in orthotopic patient-derived xenografts (PDXs) of HER2-positive and HER2-low breast cancer brain metastases (BCBM). Separately, we evaluated the effects of T-DXd in a retrospective cohort study of 17 patients with stable or active brain metastases.
RESULTS: T-DXd inhibited tumor growth and prolonged survival in orthotopic PDX models of HER2 positive (IHC 3+) and HER2 low (IHC 2+ / FISH ratio < 2) BCBMs. T-DXd reduced tumor size and prolonged survival in a T-DM1 resistant HER2-positive BCBM PDX model. In a retrospective multi-institutional cohort study of 17 patients with predominantly HER2-positive BCBMs, the CNS objective response rate (ORR) was 73% (11/15) while extracranial response rate was 45% (5/11). In the subset of patients with untreated or progressive BCBM at baseline the CNS ORR was 70% (7/10). The median time on treatment with T-DXd was 8.9 (1.3-16.2) months with 42% (7/17) remaining on treatment at data cutoff.
CONCLUSIONS: T-DXd demonstrates evidence of CNS activity in HER2-positive and HER2-low PDX models of BCBM and preliminary evidence of clinical efficacy in a multi-institution case series of patients with BCBM. Prospective clinical trials to further evaluate CNS activity of T-DXd in patients with active brain metastases are warranted.

DOI: https://doi.org/10.1158/1078-0432.CCR-22-1138